We have shown that patients with hypercholesterolemia have reduced responses to the endothelium-dependent agent, acetylcholine. Other investigators had also shown depressed responses to methacholine. However, the endothelium-dependent vascular responses to non-muscarinic agents have not been investigated in hypercholesterolemic patients. Therefore, to determine whether the impaired endothelial function of hypercholesterolemic patients is related to a specific defect at the level of the muscarinic receptor in the endothelial cell, we studied the responses to acetylcholine, sodium nitroprusside (an endothelium- independent dilator) and substance P (an endothelium-dependent dilator that acts on a nonmuscarinic receptor). Studies were performed in 14 hypercholesteremic patients (6 male; age 52+/-6 years) and 14 normal controls (6 males; age 48+/-8 years). Drugs were infused into the brachial artery and forearm blood flow was measured by strain gauge plethysmography. Compared to normal controls, hypercholesterolemic patients had a reduced response to acetylcholine and also to substance P. No significant difference, however, was observed in the vasodilator response to sodium nitroprusside. Thus, the impaired endothelium- dependent vasodilator response of hypercholesterolemic patients extends to nonmuscarinic agents. This indicates that the endothelial dysfunction characteristic of this condition is not isolated to the muscarinic receptor, and therefore involves a broader abnormality of the vascular endothelium.